Over the past 20 years, the arcuate nucleus melanocortin system emerged as a crucial regulator of feeding and energy metabolism. A yin-yang relationship between orexigenic AgRP and anorexigenic POMC neurons has been considered a primum movens in control of whole body metabolism. Strikingly, however, we recently discovered that activation of POMC neurons by cannabinoid receptor 1 (CB1R) is associated with increased feeding, and, that POMC neuronal activation is crucial for cannabinoid-induced feeding. Our observations suggest that the orexigenic tone of POMC neurons rely on switching vesicular release of ?-MSH to ?-endorphin. Indeed, inhibition of opiate receptors in the brain diminished cannabinoid-induced feeding. We also found that CB1R activation-induced feeding is associated whit uncoupling protein 2 (UCP2)-dependent mitochondrial dynamics in the hypothalamus, of which selective impairment by knocking down UCP2 abolished CB1R-induced feeding. These observations gave impetus to the hypothesis that cell autonomous expression of CB1R and UCP2 in POMC neurons are critical for CB1R-induced feeding and that this behavioral response relies on POMC-released ?-endorphin. We also predict that POMC-driven feeding occurs in physiological circumstances. For example, elevated endogenous cannabinoid levels coincide with activation of POMC neurons after feeding initiation subsequent to a prolonged fast as well as in diet-induced obese mice. We hypothesize that an orexigenic POMC tone, utilizing the mechanisms described above, is an important element in rebound feeding after food deprivation and in high fat diet-induced obesity. We will test our hypotheses by utilization of unique transgenic mice lines in combination with state-of- the art neurobiological, cellular biological, biochemical and physiological approaches. With the execution of these studies, we will deliver an entirely novel aspect of feeding regulation by the POMC system with immediate implications to physiology and disease states of metabolism.